This project is aimed at gaining an understanding of the relationship between pyrimidine nucleoside conformation and enzyme specificity, with the premise that such knowledge will aid in the design of more specific anti-tumor nucleosides. For this purpose, we are preparing a series of pyrimidine nucleosides that are restrained to known conformations while maintaining a full complement of hydrogen-bonding sites. Among the compounds currently under investigation are 6,5'-cyclopyrimidine nucleosides, 5'-hydroxymethyl-6,5'-cyclonucleosides and 6-CH2-5'-cyclonucleosides. These compounds occupy varying positions within the anti-conformational range, and their 5'-hydroxy and hydroxymethyl groups simulate the gauche-trans or trans-gauche conformers of ordinary nucleosides. The ability of these compounds to act as substrates and/or inhibitors of a number of enzymes important in cancer chemotherapy will be evaluated--for example, pyrimidine nucleoside kinases and deaminases. Routine screening of the new cyclonucleosides for anti-tumor and anti-viral activity will be examined.